Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics.

The Physiopathology of T- Cell Acute Lymphoblastic Leukemia: Focus on Molecular Aspects

“…The constitutive activation of PI3K/AKT/mTOR signaling pathway may also be targeted: several PI3K inhibitors showed antileukemic effects in T-ALL cell lines, whereas mTOR inhibitors seem to prolong survival in T-ALL cells (34). The most studied molecules were everolimus and temsirolimus (106), that induced variable responses (0-50%) in association to chemotherapy and in a small number of cases (94)(95)(96). The limited efficacy of mTOR inhibitors seems to be linked to the activation of compensatory signaling pathways (106).…”

“…The most studied molecules were everolimus and temsirolimus (106), that induced variable responses (0-50%) in association to chemotherapy and in a small number of cases (94)(95)(96). The limited efficacy of mTOR inhibitors seems to be linked to the activation of compensatory signaling pathways (106). Furthermore, dual PI3K/mTOR inhibitors, NVP-BEZ235 and NVP-BKM120, have been studied.…”

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

“…Phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β‐catenin signaling pathways are implicated in healthy T‐cell development, whereas aberrations such as mutations, deletions, or overexpression of components belonging to the aforementioned networks contribute to T‐ALL pathogenesis (Bongiovanni, Saccomani, & Piovan, ; Evangelisti, Chiarini, McCubrey, & Martelli, ; Martelli et al, ; McCubrey et al, ).…”

“…such as mutations, deletions, or overexpression of components belonging to the aforementioned networks contribute to T-ALL pathogenesis (Bongiovanni, Saccomani, & Piovan, 2017;Evangelisti, Chiarini, McCubrey, & Martelli, 2018b;Martelli et al, 2019;McCubrey et al, 2014).…”

“…It is well known that high levels of the aforementioned genes are found in several types of cancer (Velculescu et al, 1999). Of note, c-myc is a direct target of the Wnt/β-catenin pathway, as well as of Notch1 signaling, the most frequently mutated signaling network in T-ALL (Evangelisti et al, 2018b). c-myc activation is involved in tumor initiation, progression, and maintenance (Dang, 2012).…”